129

CAB International 2000. Breeding for Disease Resistance in Farm Animals

(eds R.F.E. Axford, S.C. Bishop, F.W. Nicholas and J.B. Owen)
6
Genetics of Helminth
Resistance
L.C. Gasbarre
1
and J.E. Miller
2
1
USDA-ARS, LPSI, Immunology and Disease Resistance
Laboratory, Beltsville Agricultural Research Center, Beltsville, USA;
2
Department of Epidemiology and Community Health, School of
Veterinary Medicine and Department of Animal Science, Louisiana
State University, Baton Rouge, USA
Summary
Gastrointestinal (GI) nematodes disrupt nutrient utilization of grazing Gastrointestinal (GI) nematodes disrupt nutrient utilization of grazing Gastrointestinal (GI) nematodes disrupt nutrient utilization of grazing Gastrointestinal (GI) nematodes disrupt nutrient utilization of grazing Gastrointestinal (GI) nematodes disrupt nutrient utilization of grazing
ruminants, resulting in reduced growth and productivity by the infected ruminants, resulting in reduced growth and productivity by the infected ruminants, resulting in reduced growth and productivity by the infected ruminants, resulting in reduced growth and productivity by the infected ruminants, resulting in reduced growth and productivity by the infected
animals. Anthelminthic drug treatment presents a number of problems, animals. Anthelminthic drug treatment presents a number of problems, animals. Anthelminthic drug treatment presents a number of problems, animals. Anthelminthic drug treatment presents a number of problems, animals. Anthelminthic drug treatment presents a number of problems,
including that of drug-resistant parasites. An alternative to complete including that of drug-resistant parasites. An alternative to complete including that of drug-resistant parasites. An alternative to complete including that of drug-resistant parasites. An alternative to complete including that of drug-resistant parasites. An alternative to complete
reliance on drugs is the use of naturally occurring resistance to the parasites. reliance on drugs is the use of naturally occurring resistance to the parasites. reliance on drugs is the use of naturally occurring resistance to the parasites. reliance on drugs is the use of naturally occurring resistance to the parasites. reliance on drugs is the use of naturally occurring resistance to the parasites.
Studies of both small ruminants and cattle indicate that a substantial Studies of both small ruminants and cattle indicate that a substantial Studies of both small ruminants and cattle indicate that a substantial Studies of both small ruminants and cattle indicate that a substantial Studies of both small ruminants and cattle indicate that a substantial
component of the variance in the level of infection to these parasites is due component of the variance in the level of infection to these parasites is due component of the variance in the level of infection to these parasites is due component of the variance in the level of infection to these parasites is due component of the variance in the level of infection to these parasites is due
to host genetic components. The effect of host genetics on resistance to GI to host genetic components. The effect of host genetics on resistance to GI to host genetic components. The effect of host genetics on resistance to GI to host genetic components. The effect of host genetics on resistance to GI to host genetic components. The effect of host genetics on resistance to GI
nematodes appears to be of the same magnitude across a number of nematodes appears to be of the same magnitude across a number of nematodes appears to be of the same magnitude across a number of nematodes appears to be of the same magnitude across a number of nematodes appears to be of the same magnitude across a number of
mammalian species, with an estimated heritability of approximately 0.3. mammalian species, with an estimated heritability of approximately 0.3. mammalian species, with an estimated heritability of approximately 0.3. mammalian species, with an estimated heritability of approximately 0.3. mammalian species, with an estimated heritability of approximately 0.3.
However, much variation exists. For example, determinations of the number However, much variation exists. For example, determinations of the number However, much variation exists. For example, determinations of the number However, much variation exists. For example, determinations of the number However, much variation exists. For example, determinations of the number
of parasite eggs passed in the faeces is a good indicator of parasite burdens of parasite eggs passed in the faeces is a good indicator of parasite burdens of parasite eggs passed in the faeces is a good indicator of parasite burdens of parasite eggs passed in the faeces is a good indicator of parasite burdens of parasite eggs passed in the faeces is a good indicator of parasite burdens
in sheep in areas where in sheep in areas where in sheep in areas where in sheep in areas where in sheep in areas where Haemonchus contortus is the major problem, but a is the major problem, but a is the major problem, but a is the major problem, but a is the major problem, but a
very poor indicator in cattle in areas where very poor indicator in cattle in areas where very poor indicator in cattle in areas where very poor indicator in cattle in areas where very poor indicator in cattle in areas where Ostertagia ostertagi is the is the is the is the is the
dominant pathogen. Similarly, immune effector mechanisms that affect dominant pathogen. Similarly, immune effector mechanisms that affect dominant pathogen. Similarly, immune effector mechanisms that affect dominant pathogen. Similarly, immune effector mechanisms that affect dominant pathogen. Similarly, immune effector mechanisms that affect
intestinal-dwelling worms may be less effective on abomasal-dwelling intestinal-dwelling worms may be less effective on abomasal-dwelling intestinal-dwelling worms may be less effective on abomasal-dwelling intestinal-dwelling worms may be less effective on abomasal-dwelling intestinal-dwelling worms may be less effective on abomasal-dwelling
parasites. Economically feasible tools are needed to identify accurately parasites. Economically feasible tools are needed to identify accurately parasites. Economically feasible tools are needed to identify accurately parasites. Economically feasible tools are needed to identify accurately parasites. Economically feasible tools are needed to identify accurately
animals with enhanced or diminished resistance to the parasites. animals with enhanced or diminished resistance to the parasites. animals with enhanced or diminished resistance to the parasites. animals with enhanced or diminished resistance to the parasites. animals with enhanced or diminished resistance to the parasites.
Fortunately, the distribution of the parasites is such that control could be Fortunately, the distribution of the parasites is such that control could be Fortunately, the distribution of the parasites is such that control could be Fortunately, the distribution of the parasites is such that control could be Fortunately, the distribution of the parasites is such that control could be
accomplished by targeting a small percentage of susceptible animals for accomplished by targeting a small percentage of susceptible animals for accomplished by targeting a small percentage of susceptible animals for accomplished by targeting a small percentage of susceptible animals for accomplished by targeting a small percentage of susceptible animals for
manipulation, treatment or removal. Marker-assisted selection could be used manipulation, treatment or removal. Marker-assisted selection could be used manipulation, treatment or removal. Marker-assisted selection could be used manipulation, treatment or removal. Marker-assisted selection could be used manipulation, treatment or removal. Marker-assisted selection could be used
to develop genetic markers for susceptibility or resistance and to use these to develop genetic markers for susceptibility or resistance and to use these to develop genetic markers for susceptibility or resistance and to use these to develop genetic markers for susceptibility or resistance and to use these to develop genetic markers for susceptibility or resistance and to use these
to make breeding and treatment decisions, including introgression of to make breeding and treatment decisions, including introgression of to make breeding and treatment decisions, including introgression of to make breeding and treatment decisions, including introgression of to make breeding and treatment decisions, including introgression of
desirable alleles into susceptible populations. A more long-term approach is desirable alleles into susceptible populations. A more long-term approach is desirable alleles into susceptible populations. A more long-term approach is desirable alleles into susceptible populations. A more long-term approach is desirable alleles into susceptible populations. A more long-term approach is
to identify and characterize the loci associated with immunity through the to identify and characterize the loci associated with immunity through the to identify and characterize the loci associated with immunity through the to identify and characterize the loci associated with immunity through the to identify and characterize the loci associated with immunity through the
use of candidate genes and linkage analyses to produce animals of the use of candidate genes and linkage analyses to produce animals of the use of candidate genes and linkage analyses to produce animals of the use of candidate genes and linkage analyses to produce animals of the use of candidate genes and linkage analyses to produce animals of the
desired phenotype. desired phenotype. desired phenotype. desired phenotype. desired phenotype.
130 L.C. Gasbarre and J.E. Miller
Introduction
By far the most important helminth infections of livestock are infections of
grazing ruminants by nematodes residing within the gastrointestinal (GI) tract
of the vertebrate host. Because these are the most economically important
helminth parasitoses, they have received the bulk of attention both in terms of
research efforts, and in terms of commercial interest in products to control
infection. This chapter will focus on the genetics of resistance to these
important pathogens, and the potential means by which these infections can
be controlled through manipulation of the ruminant genome. Because the
biology of the parasites differs substantially between GI nematodes of cattle
and those of small ruminants (i.e. sheep and goats), there are significant
differences in the way that host genetics could be used to reduce the economic
impact of the parasites. For this reason, we will address the genetics of
resistance to GI nematodes of small ruminants and of cattle as separate topics.
Biology of GI Nematode Infections
To use host genetics to control infections by GI nematodes it is important to
understand the hostparasite interaction in order to identify points of contact
between the parasite and its host that can be successfully manipulated to the
detriment of the parasite. GI nematode infections of ruminants remain a major
constraint to the efficient raising of livestock throughout the world. In the
USA alone it is estimated that these parasites cost the American livestock
industry in excess of US$2 billion per year in lost productivity, and in in-
creased operating expenses.
Historically, control of these parasites was accomplished by complicated
management programmes that kept stocking rates low or attempted to mini-
mize the exposure of susceptible animals to heavily infected pastures. Under
favourable conditions these programmes were capable of reducing the occur-
rence of large outbreaks of clinical illness in livestock herds. But these systems
were inefficient, they did not reduce production losses due to subclinical levels
of infection and they often failed when conditions for parasite transmission
were optimal. This is especially true in small ruminants, where GI nematodes
are often one of the most important impediments to the successful raising of
the animals (American Association of Veterinary Parasitologists, 1983).
Approximately 2030 years ago anthelmintic agents began to appear that
had both low toxicity for the ruminant host and high efficacy against the
parasites. As these drugs became available, producers became less and less
concerned with traditional parasite control programmes, and more and more
dependent on the anthelmintics for control. Although modern anthelmintics
have been an important tool for cattle raisers, a number of factors have arisen
recently that illustrate that to depend on the drugs as a sole means of parasite
control is a serious mistake. The most important of these factors has been the
appearance throughout the world of parasites resistant to the anthelmintics.
In small ruminants, parasites have developed resistance against all classes of
Genetics of Helminth Resistance 131
anthelmintics currently employed, and resistance to multiple classes of drugs
by the same parasite is commonplace (Waller and Prichard, 1986; Prichard,
1990; Windon, 1991; Waller, 1994). While such resistance is less common in
parasites of cattle, there are reports of resistance in New Zealand (Vermunt et
al., 1995; Hosking et al., 1996) and in South America (Pinheiro and Echevarria,
1990). A second concern about this dependence on anthelmintics is the grow-
ing insistence of consumers that their food and environment be free of chemi-
cal residues (Herd et al., 1993). The growing number of organic producers find
repeated anthelmintic use to be an unacceptable means of parasite control.
The third factor affecting current control programmes is the movement
towards more intensive grazing programmes for livestock. Increased grazing
intensity is the result of several factors. One impetus is the reduction of the
amount of land available for grazing due to forces such as urban development
and the setting aside of lands for recreational or conservational use. A second
factor is the realization that intensive grazing programmes can result in higher
net profits for small farmers, coupled with the perception that grazing systems
are more sustainable systems. This move towards more intense use of past-
ures will necessitate more frequent use of anthelmintics, further increasing the
chances for selection of anthelmintic resistance in the parasite populations.
The parasites have a simple life cycle, beginning with adult male and
female worms in the alimentary tract of the host. Fertilized eggs are passed in
the faeces. The eggs hatch and larval development begins within the pro-
tective environment of the faecal pat or droppings. Depending upon ambient
temperature, the larvae reach the infective third larval stage approximately
1014 days after being passed in the faeces. The infective larvae are carried
away from the faeces by forces such as rain, and are then found on the grass to
await ingestion by the foraging host. Upon ingestion the larvae undergo an
additional two moults to the adult stage. In general, the developing larvae are
found in more intimate contact with host mucosal surfaces than are the more
lumenal-dwelling adult worms.
While on pasture the larvae are very susceptible to desiccation, and
transmission is very low to non-existent during very dry periods. In addition,
transmission is reduced during periods of persistent cold. For some species this
is due to killing of the larvae, but in other cases it is more a reflection of reduced
grazing due to dormancy of the grasses. While in the host, most parasites are
susceptible to host immune responses. These responses range from those that
alter parasite morphology or physiology to those that protect the host from
reinfection, presumably by killing of the developing worms or exclusion of the
invasive third-stage larvae. Most of the genera of parasites found in ruminants
stimulate a relatively effective level of immunity in most animals after several
months on pasture. This immunity significantly reduces the number of worms
that become established in the grazing animals. The exceptions to this are
Ostertagia ostertagi in cattle and Haemonchus contortus in sheep. Cattle remain
susceptible to infection by Ostertagia for many months, and immunity that
actually reduces the development of newly acquired larvae is usually not evident
until the animals are more than 2 years old. In sheep, lambs under the age of
about 8 months do not develop significant protective immune responses to
132 L.C. Gasbarre and J.E. Miller
infection or immunization (Urquhart et al., 1966; Knight and Rodgers, 1974).
This prolonged susceptibility to reinfection is a major reason why these
parasites remain the most economically important GI nematodes in their
respective species. Although animals may remain susceptible to reinfection for
a prolonged period of time, in cattle there is a stunting of newly acquired
worms and, in addition, the female worms produce significantly fewer eggs
than do female worms in a primary infection. The overall result of either type
of immunity is a reduction in parasite transmission.
Given the ubiquitous nature of GI nematodes, the fact that wild ungulates
may serve as a source of infection, and that optimal conditions for parasite
transmission are the same as optimal conditions for grass growth, it is virtually
impossible to eradicate GI nematodes in grazing ruminants. Rather than
eradication, the goal of effective nematode control programmes is to protect
animals from production losses by reducing parasite transmission and estab-
lishment in the host. One such approach is to use genetically superior stock as
an adjunct to current methods of control.
Enhancing Helminth Resistance in Small Ruminants
Sources of genetic variation
It may not be possible, or even desirable, to identify animals which have
complete genetic resistance to nematode infection, but there is considerable
evidence that part of the natural variation in resistance is under genetic
control (reviewed by Wakelin, 1978; Barger, 1989; Stear et al., 1990a; Gray and
Gill, 1993; Raadsma et al., 1997a; Stear and Wakelin, 1998). Selection of resist-
ant animals within breeds or incorporating resistant breeds into breeding
programmes are the available options. Traditional breeding programmes and
selection for nematode resistance have been used successfully to establish
flocks of sheep with high levels of resistance (Windon and Dineen, 1984;
Albers et al., 1987; Windon, 1990, 1991; Woolaston et al., 1990, 1991). A
thorough summary of responses achieved in these programmes is given by
Morris (1998). Identification of some of the genes involved in regulating
resistance will allow earlier selection of genetically superior animals and may
increase the rate of selection for resistance.
Within breed
There is variation in nematode burdens between individual sheep in a flock
grazing the same pastures. The distribution of burdens (and faecal egg count,
FEC) is overdispersed; that is, a minority of the individuals harbour the
majority of the nematodes. Evidence for genetic variation in such distributions
comes from studies of pedigree populations in which offspring have been
assessed for resistance under uniform conditions of exposure and at the same
age. Examples of the heritability of resistance to infection in sheep, as
measured by FEC, varied from 0.22 to 0.43. Albers et al. (1987) challenged 882
lambs with 11,000 H. contortus larvae and estimated the heritability of FEC 4
Genetics of Helminth Resistance 133
weeks after challenge as 0.34 0.10 (mean standard error). Woolaston et al.
(1991) reported estimated heritabilities, after artificial challenge with H. con-
tortus, of FEC in three flocks of Merino sheep as 0.27 0.13, 0.22 0.04 and
0.31 0.03. Cummings et al. (1991) reported estimated heritability, after natur-
ally acquired Ostertagia infection, of FEC in Merino sheep as 0.42 0.14. Baker
et al. (1991) reported estimated heritability, after naturally acquired mixed
species infection, of FEC in Romney sheep as 0.34 0.19. Other reports of
heritable variation in FEC include Bishop et al. (1996), Bisset et al. (1992), Douch
et al. (1995), McEwan et al. (1992, 1995), Morris et al. (1997a, b), Stear et al.
(1997), Woolaston and Eady (1995) and Woolaston and Piper (1996). Stear et al.
(1997) showed that for 6-month-old lambs facing Ostertagia infection, it was
worm size and fecundity rather than worm burden that was the heritable trait.
At these established levels of heritability, there are prospects for selective
breeding for improved resistance at least in the sheep industry (Gray, 1991).
As a result of these encouraging research findings, there are now structured
breeding programmes for resistance to parasites within commercial sheep
flocks in both New Zealand and Australia.
Studies conducted in Fiji (humid Pacific island conditions) indicated that
the heritability of FEC in Fijian goats from two locations was not significantly
different from 0 (Woolaston et al., 1995). On the other hand, heritability of FEC
in the crossbred sheep population was estimated at 0.23 0.07. Therefore it
was concluded that within-breed genetic improvement for resistance to nema-
tode infection was not feasible for goats, but had potential for sheep.
Between breeds
Some breeds of sheep are more resistant than others to nematode infection.
For example, Scottish Blackface sheep are more resistant than Finn-Dorset
sheep to H. contortus infection (Altaif and Dargie, 1978) and the Red Maasai
sheep of Kenya are more resistant than breeds imported into Kenya (Preston
and Allonby, 1978, 1979a; Bain et al., 1993; Baker et al., 1993; Miller et al.,
1995). In France, Gruner et al. (1986) showed that Romanov sheep were more
susceptible than Lacaune sheep to infections with Nematodirus spathiger and
Ostertagia circumcincta. In the USA, Radhakrishnan et al. (1972) showed that
Florida Native lambs were more resistant to H. contortus infection than Ram-
bouillet lambs. Courtney et al. (1985) subsequently showed that St Croix lambs
were more resistant than Florida Native and Barbados Blackbelly lambs, which
in turn were more resistant than domestic crossbred (Suffolk, Finn-Dorset, and
Rambouillet) lambs. Gamble and Zajac (1992) showed that St Croix sheep were
more resistant than Dorset sheep. Bahirathan et al. (1996) and Miller et al.
(1998) have shown that Gulf Coast Native sheep are more resistant than
Suffolk sheep. In Indonesia, Gatenby et al. (1995) and Romjali et al. (1997)
found that introduced St Croix ewes were more resistant than the local
Sumatra ewes. Moreover, crosses of St Croix and Barbados Blackbelly (also
introduced) with local Sumatra sheep were at least as resistant or more resist-
ant than pure Sumatra sheep and could be used to improve production (body
size). Further evidence for other breed differences are summarized in Gruner
and Cabaret (1988), Gray (1991) and Zajac (1995).
134 L.C. Gasbarre and J.E. Miller
Selection for resistance
For any selection programme to be successful it is essential that the superior
individuals can be identified accurately and economically from among the
candidate breeding stock. There are direct and indirect means to help make
those selections.
Direct selection
There is only one direct way to measure nematode burdens and that is by
recovery at necropsy, but it is obvious that this method cannot be employed as
a selection criterion. Faecal egg counts have been shown to have moderate
(0.61) to high (0.91) correlation with nematode burdens (Baker et al., 1991;
Stear et al., 1995a; Bisset et al., 1996), and in essence might be considered a
direct measure of infection. The most effective and only practical way to esti-
mate potential pasture contamination is from FEC and, in one sense, this is
also direct selection.
Experimental selection programmes for establishing resistant and sus-
ceptible lines of sheep have been in place in Australia and New Zealand for
several years, where selection has been based on FEC after natural infection
and artificial challenge. The rate of selection progress is determined by the
flock generation interval, the heritability of resistance and the intensity of
selection. It is more efficient if selection of breeding animals can be made at an
early age, but it is possible that lambs may need to be primed during their first
natural exposure or with initial artificial infections (36 months of age) to
initiate an immune response (Woolaston et al., 1991). This concept was
supported by work demonstrating that no genetic differences were apparent
at the sire level or the bloodline level in weaners raised parasite-free and
experimentally infected with H. contortus. This phenomenon was verified
using trickle infections in resistant and susceptible lines (Windon, 1991). Simi-
lar observations were noted under natural exposure conditions from birth with
Gulf Coast Native and Suffolk sheep (Bahirathan et al., 1996). In this experi-
ment, both Suffolk and Gulf Coast Native lambs had similar increasing H.
contortus levels until 810 weeks of age. Subsequently, the infection level in
Gulf Coast Native lambs decreased and in Suffolk lambs it continued to
increase. It appeared that resistance was acquired in Gulf Coast Native lambs,
but not Suffolk lambs, after being primed, but at an earlier age than would be
considered normal for an immune response to infection in lambs (Barger, 1988).
Indirect selection
In the context of breeding for resistance, all criteria except those that measure
burdens directly must be considered indirect. These indirect selection criteria
may include continuously variable physiological or immunological traits, which
are referred to as indicator traits, or polymorphisms of single genes or small
groups of linked genes, which are referred as genetic markers.
INDICATOR TRAITS. Indicator traits usually reflect host response to infection. In
living animals, such traits might include blood levels of eosinophils and anti-
Genetics of Helminth Resistance 135
nematode antibodies, and blood packed-cell volume (PCV). Dawkins et al.
(1989) and Buddle et al. (1992) reported blood eosinophilia associated with T.
colubriformis infection in selected lines of resistant compared to susceptible
sheep. In contrast, Douch et al. (1996) and Woolaston et al. (1996) reported
several studies indicating that blood eosinophil level was variable and in-
consistent for T. colubriformis and H. contortus resistant and susceptible lines
of sheep, which reduced its potential use as an indicator.
Bissett et al. (1996) reported that Romney lambs selectively bred for
resistance had significantly higher serum T. colubriformis-specific antibodies,
IgG1 and IgM, than in susceptible lambs. Douch et al. (1996) also suggested
that antibody levels (particularly IgG1) to excretory or secretory antigens of
T. colubriformis L3 may be useful in selecting resistant animals. In two trials to
test this selection criterion, lambs from rams with high and low antibody levels
showed that lines bred true for antibody level but that there was no difference
in FEC, which diminished any genetic relationship. Blood PCV may be useful
for selecting H. contortus resistant animals, as anaemia is a classic sign of
haemonchosis, but no studies have been conducted to evaluate this criterion.
For Ostertagia infections, there is evidence that IgA may be a major regulator
of worm length, hence FEC, and therefore a potential indicator trait (Stear et
al., 1995a).
Other indicator traits that cannot be evaluated in living animals are
accumulation of immune-mediated cell types (specifically mucosal mast cells
(MMC), globule leucocytes and eosinophils) in the GI mucosa. At necropsy,
increased levels of these cell types have been observed in resistant lines and
breeds (Presson et al., 1988; Gamble and Zajac, 1992; Gill et al., 1993).
If immune-mediated indicator traits are to be useful for resistance selec-
tion purposes, resistance has to be an acquired phenomenon. Expression of
resistance in sheep selected for resistance to H. contortus as an acquired
immune response has been investigated in Merino sheep. Gill (1991) found that
primary infections in parasite-free lambs from resistant and random-bred lines
resulted in no significant difference between nematode burdens, serum anti-
body levels, MMC or circulating and tissue eosinophils between the two
groups. However, there was a significant difference in FEC, with lambs of re-
sistant lines having higher levels. Following removal of nematode burdens by
anthelmintic treatment, challenge infections resulted in the lambs of resistant
lines having significantly lower FEC and nematode burdens and significantly
higher serum antibody levels, MMC hyperplasia and mucosal eosinophilia.
Additional support for the immunological basis of helminth resistance comes
from work done on immunosuppression and ablation of CD4
+
T cells. Presson
et al. (1988) demonstrated that immunosuppression of resistant wethers
with dexamethasone resulted in abolishing the differences between them and
random-bred susceptible wethers. Gill et al. (1993) selectively depleted
genetically resistant Merino lambs of their CD4
+
T cells, by treatment with
mouse monoclonal antibody specific for the determinant, before and during
challenge infection with H. contortus. Treated lambs lost their expression of
genetic resistance as they had higher FEC and nematode burdens compared to
control random-bred susceptible lambs. The MMC hyperplasia and tissue
136 L.C. Gasbarre and J.E. Miller
eosinophilia associated with resistance were also suppressed in treated lambs.
These results suggest that CD4 T cells play a role in mediating genetic resist-
ance. It was hypothesized that these CD4 T cells respond to presentation of
antigen in the context of class II MHC molecules and produce various cyto-
kines that amplify and regulate the recruitment, differentiation and prolifer-
ation of effector cells, such as mast cells, globule leucocytes, eosinophils and
antibody-secreting cells. Gill (1994), using lymphocyte proliferation and skin
hypersensitivity responses to H. contortus antigens, demonstrated a cell-
mediated immune component in resistant lambs. Bissett et al. (1996) also
reported further evidence to support an acquired immune-mediated response
in Romney lambs selectively bred for resistance, where numbers of globule
leucocytes/MMC were significantly higher in resistant lambs than in
susceptible lambs. In contrast, Miller et al. (1996) found that depletion of CD4
+
T cells did not abrogate resistance in Gulf Coast Native sheep, suggesting that
there may not be a major acquired immune mechanism involved in resistant
breeds of sheep.
GENETIC MARKERS. Recognition of resistance has relied on observed pheno-
typic variation. It is not known whether this resistance is conferred by a small
number of genes or a larger number of genes, each having somewhat smaller
effects. In either case, genetic maps are necessary to identify genes directly
mediating resistance or markers linked to those genes. Two strategies can be
used to identify genes influencing resistance. The first does not require an
existing genetic map, and uses the analysis of candidate genes, which are
expressed genes that may be expected to play a role in regulating resistance
(i.e. genes encoding immunoglobulins, MHC antigens, T-cell receptor mole-
cules, etc.). The second relies upon linkage maps and genome-wide analyses
for quantitative trait loci (QTL) detection. This method is based upon the use
of polymorphic DNA markers to tag specific genes or regions of the genome
carrying resistant genes.
The first genetic marker suggested for use in selection for resistance was
haemoglobin type. Sheep have two alleles (A and B) for haemoglobin and
several studies indicated that animals with haemoglobin type AA (HbAA)
were more resistant than HbAB, which were more resistant than HbBB to
infection with H. contortus and its effects (Allonby and Urquhart, 1976; Altaif
and Dargie, 1978; Preston and Allonby, 1979b). However, other workers were
unable to confirm that association (Radhakrishnan et al., 1972; Riffkin and
Yong, 1984; Albers and Gray, 1986; Kassai et al., 1990). Therefore, no general
conclusion can be drawn concerning the usefulness of haemoglobin type as a
predictive marker for resistance, at least to H. contortus.
A second attempt at using the candidate gene approach was the investi-
gation of the major histocompatibility complex (MHC). This is logical because
MHC class I and class II genes are involved in immune responses. The MHC
regulates resistance to nematode infections in experimental mice (Wassom et
al., 1979; Wassom and Kelly, 1990), guinea-pigs (Geczy and Rothwell, 1981) and
swine (Bell et al., 1982; Wakelin and Donachie, 1983; Lunney and Murrell,
1988; Madden et al., 1990). Outteridge et al. (1985, 1986, 1988) reported an
Genetics of Helminth Resistance 137
association between class I antigens of the ovine MHC and response to chal-
lenge with T. colubriformis. Cooper et al. (1989), however, found no evidence
for an association between class I antigens of the ovine MHC and suscept-
ibility to H. contortus infection in the progeny of six rams. Stear et al. (1988,
1990b) showed that the bovine MHC is one of the genetic systems that may be
involved in regulating resistance to nematode infection. Evidence for class II
gene association with parasite resistance in sheep is scarce, but increasing.
Hulme et al. (1991) reported that restriction fragment length polymorphism
(RFLP) analyses using cross-hybridizing human MHC DQA, DQB and DRB
cDNA probes showed that genes in or closely linked to the MHC have a signi-
ficant effect on resistance to T. colubriformis infection. Blattman et al. (1993)
showed no association between MHC class II polymorphism, detected by simi-
lar human probes, and resistance to H. contortus in a single family of parasite-
resistant Merino sheep. Grain et al. (1993) demonstrated RFLP of DQB and
DRB class II genes of the ovine MHC using ovine probes specific for the
second exons of Ovar-DQB and Ovar-DRB genes. Miller et al. (1995) demon-
strated similar polymorphisms in DQB and DRB genes of the ovine MHC
using bovine MHC probes (Muggli-Cockett and Stone, 1991), where allele
frequency was significantly different between Red Maasai compared to Dorper
breeds of sheep. However, no genetic association with parasite resistance was
investigated. Finally, Schwaiger et al. (1995) demonstrated a significant associ-
ation between a DRB1 allele and low faecal egg counts following natural
Ostertagia infection. The definition and role of the MHC in livestock species
has been reviewed (Stear et al., 1989; Wetherall and Groth, 1992; and, most
recently, in this volume).
With the advent of the polymerase chain reaction (PCR) for amplification
of genomic DNA, more efficient genetic characterization is possible. This has
led to the development of microsatellite markers and, ultimately, genetic
linkage maps. Efforts to establish a sheep gene map (by AgResearch, New
Zealand; CSIRO and the University of Melbourne, Australia; USDA, USA) has
resulted in the derivation of polymorphic markers covering the sheep genome.
The first linkage map published (Crawford et al., 1995) included 246 (pre-
dominantly microsatellite) markers. Currently there are over 550 such markers
(DeGotari et al., 1998). Because of the high degree of homology at the DNA
level between cattle and sheep, many cattle microsatellite markers have been
positioned in the sheep genome. It is generally accepted that 150300
markers evenly distributed across the genome are reasonable for a primary
linkage map (Teale, 1991), which can be used to detect quantitative trait loci, in
this case, for nematode resistance. This led to the reporting of several QTL for
nematode resistance at the ISAG meeting in August, 1998.
Ultimately, transgenic technology may be a possibility. If single or multiple
genes responsible for expression of nematode resistance can be identified,
then transfer of such genes from resistant to susceptible individuals may pro-
vide a more long-lasting resistance, since they provide much more of an evo-
lutionary challenge to the parasite.
138 L.C. Gasbarre and J.E. Miller
Objectives of selection for resistance
It is unlikely that a breeding programme would have resistance to parasites as
its sole objective. More likely the objective would be expressed in units of
production or in the value of production. Therefore, genetic relationships with
other traits in the objective, for example liveweight gain, fleece weight or
resistance to other diseases, may be as important, or more important, than
resistance itself.
Similarly, the usefulness of resistant breeds depends on the commercial
requirements of the producer. If resistant breeds are better producers of meat
or wool than breeds in current use, then a change to the resistant breed may
be advantageous. Comparison of the resistant Red Maasai breed with the
susceptible Dorper breed in Kenya has shown that the Red Maasai are just as
productive as the Dorpers (Baker et al., 1993, 1998). Not all such comparisons
favour the resistant breeds but detailed studies of the breed productivity,
including reproductive, survival and production characteristics, all measured in
a realistic commercial environment, are required. It should be noted that all
reports of resistant breeds do not take into account between-sire differences,
and the perceived breed difference may really be due to the effect of a few
resistant sires. In addition to their potential as productive replacements
for existing breeds, parasite-resistant breeds are of extreme interest for investi-
gating the genetic basis of resistance and how resistance genes may be
expressed.
Selection within breed has not resulted in any association with loss of
productivity (Windon and Dineen, 1984; Albers et al., 1987; Woolaston et al.,
1990). It has been suggested that selection for resistant animals actually results
in increased or no loss of production (Baker et al., 1991; Eady et al., 1994;
Morris et al., 1995). However, in general there is no consistent pattern in
the genetic correlations between FEC and productivity, with published corre-
lations ranging from strongly favourable (i.e. a large negative correlation)
(Bishop et al., 1996), through neutral or moderately favourable (Albers et al.,
1987; Bisset et al., 1992; Douch et al., 1995; Eady, 1998), to moderately un-
favourable (a positive correlation) (McEwan et al., 1992, 1995). The results of
Albers et al. (1987) imply that the genetic correlation strengthens as the para-
site challenge increases. Piper and Barger (1988), using the best-available
genetic correlations between parasite resistance and production traits, esti-
mated overall genetic improvement of about 10% per year for a typical Merino
flock. However, it should be emphasized that marginal economic gains are not
nearly as important as those from preventing devastating losses due to anthel-
mintic resistance in the parasite population.
There is encouraging evidence that genetic correlations between resist-
ance and more than one nematode parasite is positive (Windon, 1990). Lambs
resistant to Trichostrongylus also demonstrate significantly reduced FEC
after infection with other related species, including T. rugatus, T. axei and
O. circumcincta (Windon and Dineen, 1984; Windon et al., 1987). Similarly,
resistant Haemonchus selection-line lambs had reduced FEC after infection
with Trichostrongylus spp. and Ostertagia spp. (Gray et al., 1992). Heterologous
Genetics of Helminth Resistance 139
challenge infections of the Trichostrongylus and Haemonchus selection-line
lambs showed that differences between susceptible and resistant lines were
not as great after challenge with the heterologous species as that seen after
challenge with the homologous species (Windon, 1990; Woolaston, 1990).
McEwan et al. (1992) also demonstrated a significant positive genetic corre-
lation between Strongyle and Nematodirus FEC. Perhaps immunological
responses differ during infection with each species due to site location, feeding
habits, evasion strategies, etc. However, with the exception of the study of
Raadsma et al. (1997b), genetic correlations between resistance to parasitic
disease and other important sheep diseases are lacking. Raadsma et al. (1997b)
found that resistance to parasites is generally uncorrelated with resistance to
other diseases, except for a small positive correlation with resistance to
dermatophilosis.
Enhancing Helminth Resistance in Cattle
Effect of genetics on responses to cattle helminths
Any attempt to discern a genetic influence on resistance to GI nematodes
requires an accurate means by which to assess parasite burdens in the animals
tested. The most commonly used method to assess parasite burdens in
ruminants has been the enumeration of parasite eggs in the faeces, and to date
most of the work aimed at determining the role of genetics in resistance to this
group of parasites has been based on faecal egg counts (FEC). Analyses of FEC
values in cattle herds reveals several important facts. First, if calves are
sampled on consecutive days, the repeatability of FEC values is approximately
0.6 (Gasbarre et al., 1996); this repeatability decreases dramatically if the time
between samples is extended (Stear et al., 1984). Secondly, FEC values de-
crease with the age of the animal, and change throughout the year based on
grazing behaviour of the animals. Thirdly, the sex of the animal influences FEC
values, with bulls having higher FEC values than cows (Gasbarre et al., 1990;
Stear et al., 1990b). And fourthly, FEC values are not normally distributed
within a cattle herd, instead they follow an overdispersed distribution (Crofton,
1971a, b; Genchi et al., 1989; Gasbarre et al., 1993). This overdispersed
distribution is one where the value of the standard error of the mean exceeds
the value of the mean. In such a distribution most individuals have relatively
low FEC values, and a small percentage of animals are responsible for the
majority of the eggs released on the pastures. This results in an apparent
group of susceptible animals, or non-responders, whose number is usually
estimated to be between 15 and 25% of the total population (Anderson and
May, 1985; Genchi et al., 1989).
Using FEC, the role of host genetics in resistance to GI nematodes has
been investigated, both across cattle breeds and within the same breed. Suarez
et al. (1990) found that Zebu cattle had higher FEC values than did either
Hereford or Hereford Brahman crosses grazed in Argentina. It should be
noted that in this study the Zebu steers were maintained on different pastures
140 L.C. Gasbarre and J.E. Miller
than the Hereford and Hereford Brahman cross steers, so that pasture effects
would be confounded in this model. Similarly, Almeria et al. (1996) reported
that FEC values were significantly lower in Pyrenean cattle when compared
to Brown Swiss cattle when the animals were co-grazed under a traditional
mountain meadow grazing system in the Pyrenees. In contrast, studies in
Queensland, Australia, did not indicate significant breed differences in grazing
cattle (Barger et al., 1983). Looking at Angus, Hereford, Brahman, Senepol, and
Hereford Senepol and Senepol Hereford crossed yearling heifers, which
were grazed as a single group in the south-eastern USA, we found that
environmental factors greatly influenced FEC values. Because all breeds did
not exhibit the same grazing behaviour in the winter and summer, group FEC
values were strongly affected at these time points. When animals were
sampled at times of the year when grazing behaviour among the groups was
similar, we found that apparent breed differences in FEC value could be ex-
plained by sire effects within the breeds (Gasbarre, unpublished).
There is a greater body of work examining within-breed variation in FEC
values. Estimates of the heritability of FEC values have ranged from approx-
imately 0.1 to nearly 0.8 (Stear et al., 1984, 1990b; Leighton et al., 1989;
Gasbarre et al., 1990, 1993; Mackinnon et al., 1991; Kloosterman et al., 1992;
Gray and Gill, 1993; Suarez et al., 1997). The most commonly accepted esti-
mate of heritability for this trait is in the range 0.30.4. In one study covering
4 years, all calves born at the Wye Angus herd in Maryland, USA, were
intensively sampled at the time of weaning. The data were subjected to
analyses where the model accounted for variation based on age and sex of the
calf, year of sampling, potential pasture effects and sire of the calf. Because
FEC values do not follow a normal distribution, with a small number of calves
accounting for a disproportionate number of eggs released to the pasture, the
odds of a given bull producing a calf whose FEC value was in the upper 25th
percentile were calculated. Results indicated that the odds of certain bulls pro-
ducing these calves was approximately 20 times that of other bulls (Gasbarre
et al., 1995). The role of BoLA alleles in affecting FEC values is uncertain. Stear
et al. (1990b) found that two BoLA class I alleles, W7 and CA36, were related
to lower FEC values. In other studies, BoLA has been found to exhibit a very
minor effect on FEC values (Stear et al., 1984; Gasbarre, unpublished).
There is a serious problem with using FEC values to assess, under field
conditions, worm burdens in the host. Rarely, if ever, is a single parasite species
found on pastures. Most of the common parasite genera infecting cattle pro-
duce eggs that are virtually indistinguishable from each other. Among these
different genera, the fecundity of the individual species varies greatly and, even
more importantly, host factors may reduce the fecundity in some parasite
species but not in others. This is especially true for the important pathogen
Ostertagia ostertagi. Infections involving this species are characterized by the
fact that the worms are less fecund than other commonly encountered species,
and this is further compounded by the fact that host immune responses can
reduce the fecundity of the worms, without appreciable change in parasite
numbers (Smith et al., 1987; Gasbarre, 1994, 1997a). In contrast, in more tropi-
cal regions where Ostertagia is not an important component of the parasite
Genetics of Helminth Resistance 141
fauna, this may not be a serious problem (Bryan and Kerr, 1989). In temperate
regions of the world, where Ostertagia is the dominant pathogen, FEC are a
very poor indicator of numbers of Ostertagia in the host, because of the effect
on fecundity of host immunity. In temperate regions, FEC reflects the numbers
of more fecund species, such as Cooperia (Gasbarre, 1997b). This has caused
investigators to employ additional methods to attempt to estimate more
accurately the individual parasite species in the host. The most commonly
employed technique is to determine FEC values, and then culture the egg-
containing faeces. After an appropriate time interval, larval parasites that have
hatched from the eggs are recovered and identified to the genus level. Using
these procedures Suarez et al. (1997) estimated heritabilities of approximately
0.2 for Haemonchus, 0.3 for Ostertagia and Trichostrongylus and 0 for
Cooperia. In addition, Schmidt et al. (1998) did not find differences in the
diversity of parasite genera in calves from different Aberdeen Angus sires, and
concluded that the host has limited effect on diversity of parasite genera. This
implies that resistance to the different genera of parasites is similar and that
resistant individuals will be resistant across the spectra of parasite species.
Care should be exercised in interpreting the results of larval cultures, as it has
been demonstrated that culture conditions can favour the development of
some genera, potentially leading to over- or underestimates of the proportion
of the sample made up by each genus (Gasbarre, 1997c; Schmidt et al., 1998).
A second approach to the problem of different fecundities of the parasites
is to use artificial infections consisting of a single parasite. Kloosterman et al.
(1978) used this approach with artificial infections of Cooperia. In their experi-
ments they found significant differences between half-sib groups of Dutch
Friesian bull calves in FEC values, worm numbers, worm length and antibody
responses.
Another approach to addressing the problem of potential erroneous
measures of parasite burdens by FEC is to find another measure of parasite
burden, such as weight gain of the animals, serum antibody levels, serum pep-
sinogen levels, blood eosinophil numbers, etc., or to actually slaughter animals
and recover, speciate and enumerate the worms themselves. Slaughter, while it
is the most accurate, obviously greatly reduces the number of animals that can
be studied. Over the past several years we have selectively bred Angus cattle
for susceptibility or resistance to infection by gastrointestinal nematodes.
These cattle were initially derived from the Wye Angus herd, and as such, all
animals can be traced back to 1 of 18 dams or 1 of 19 bulls, with records
covering at least seven generations. All calves produced are placed at weaning
on pastures containing Ostertagia ostertagi and Cooperia oncophora. The
calves are kept on these pastures for a minimum of 120 days to allow them to
express immunity to the parasite exposure (Gronvold et al., 1992). During the
test period all animals are monitored weekly, and at the end of the test period
some animals are slaughtered for parasitological and immunological assess-
ment. Based upon the slaughter of 49 individuals the following observations
have been made. Faecal egg counts in this situation are poorly correlated with
Ostertagia numbers (R = 0.1), and are more an indication of the number of
Cooperia in the host (R = 0.6, P 0.05). The numbers of Ostertagia and
142 L.C. Gasbarre and J.E. Miller
Cooperia are significantly correlated after 1 month on pasture, but are not
significantly correlated after the 120-day test, indicating that immunity to the
two parasite genera functions differently over this time frame. Serum antibody
levels specific for the parasites (IgG1, IgG2, IgM and IgA) were not correlated
with the numbers of either parasite at slaughter. Weight gain over the entire
test was significantly correlated with the number of Ostertagia at slaughter but
not with Cooperia numbers. The number of circulating eosinophils did show a
relationship to Ostertagia numbers, but the only relationship was with peak
eosinophil numbers, meaning that animals needed to be sampled repeatedly
over time. The best indicator of Ostertagia numbers was the serum pepsino-
gen value of the animal just before slaughter (R = 0.63). Ostertagia numbers
were significantly correlated with measures of anaemia (RBC (red blood cell)
counts, haematocrit, haemoglobin levels) but this relationship was less signifi-
cant than the relationship to serum pepsinogen levels.
Because serum pepsinogen levels appeared to be the best indicator of
Ostertagia burdens, the analyses done over the 4-year period on the Wye
Angus herd were repeated, only this time assessment of heritability was
estimated on serum pepsinogen levels of each calf at weaning. The analyses
indicated that: (i) serum pepsinogen levels were not normally distributed; (ii)
serum pepsinogen levels were significantly affected by sire of the calf; and (iii)
the estimated heritability was approximately 0.3. Interestingly, the serum pep-
sinogen levels were also significantly influenced by sex of the calf, but in this
case heifer calves had higher values than bull calves. One note of caution in
using serum pepsinogen values is the fact that this relationship has only been
demonstrated in young calves. Serum pepsinogen levels are assumed to be a
measure of abomasal damage, and the subsequent release of the enzyme
precursor into the blood. It is possible that older animals could show hyper-
sensitivity to the parasites, resulting in high levels of abomasal damage with
few established worms.
The question becomes: How do these observations in an experimental
environment compare to those in a more normal field study? Stear et al.
(1990b) examined cattle from a more tropical climate, which lacked Ostertagia
but instead were infected by five species including Oesophagostomum
radiatum, which is severely pathogenic in young animals. They found that
weight gain was negatively correlated with worm numbers, but that only
Oesophagostomum numbers significantly affected weight gain. No significant
relationship was found between parasite burdens and serum antiparasite IgE
levels. In tropical cattle, Mackinnon et al. (1991) showed that whereas the
relationship between growth rate and FEC tended to be negative (favourable)
in the wet season when the worm challenge was strong, it was positive (un-
favourable) during the dry season. Almeria et al. (1996) found that the more
resistant Pyrenean cattle had higher RBC, haemoglobin and haematocrit, but
lower blood eosinophil values than the more susceptible Brown Swiss cattle.
Kloosterman et al. (1978) found significant differences in antiparasite antibody
levels among half-sib groups experimentally challenged with Cooperia, but the
relationship between FEC and antibody titre was not clear. Gasbarre et al.
(1993) found that serum antibody against parasite antigens was strongly
Genetics of Helminth Resistance 143
influenced by the sire of the calf (heritability 0.70.8), but that there was no
relationship between serum antibody levels and FEC values.
Methods by which host genetics could be used to control helminth infections
in cattle
There is sufficient genetic variation within cattle breeds in terms of their re-
sistance to nematode infection, and the heritability of this trait is high enough
that significant genetic progress can be made by classic selection programmes.
The question that arises is: Do parasites exert sufficient economic pressure to
warrant such a selection programme? The answer to this enquiry is that in
some areas there is sufficient pressure, while in others there is not. For
example, in the USA, producers in the south-east, north-east and north-west
see enough parasitism, and stocking rates are sufficiently high, that genetic
improvement in this area would increase their efficiency. In contrast, stockmen
in areas of low grazing density may not gain an advantage, although one might
still see an advantage in reducing the parasite load of animals in areas of
marginal nutrition. In addition, as questions on land use and pesticide appli-
cation become more important to consumers, programmes that reduce de-
pendence on anthelmintics will likely become more readily adopted by
producers.
A potentially more important question is whether it is wise to implement
a breeding programme based on resistance to a single disease entity.
Resistance to GI nematodes is a complex mixture of many types of immune
responses and recent work indicates that protection against the different
parasites may involve different types of immune responses (Canals et al., 1997;
Almeria et al., 1998). It is also becoming evident that different types of immune
responses, i.e. the so-called Th1 and Th2 response, are counter-regulatory.
Thus it is possible that animals that are superior in some types of responses
will be inferior in others. This, coupled with the fact that many individuals
already question the loss of diversity in agricultural species, makes it unlikely
there will be major programmes to breed for helminth resistance in cattle,
except in areas of extremely high parasite pressure.
Even though it seems unlikely that there will be major breeding pro-
grammes for helminth resistance in cattle, there are several ways host genetics
could be used to greatly increase the efficiency of cattle and dairy production.
The first is based on the fact that nematodiasis is a quantitative disease. As
parasite burdens increase, so does loss, and it is probable that very low para-
sitaemias induce little or no economic effect in otherwise well-managed
animals. With this in mind, the goal of modern parasite control programmes is
to keep transmission rates down, and not to eradicate the parasites, which is
probably impossible. The second important factor is the overdispersed nature
of nematode distributions. This pattern implies that a few members of the herd
are responsible for most of the parasite transmission. In an elegant analysis,
Anderson and May (1985) calculated that the treatment, removal or vaccin-
ation of the susceptibles would be almost as effective in controlling disease as
144 L.C. Gasbarre and J.E. Miller
would be treatment of the entire population. From an economic standpoint,
rapid and inexpensive identification of these susceptible/non-responders
could reduce treatment costs substantially. Such an approach will also lessen
the selective pressures placed on parasite populations, and should slow the
development of drug resistance in the parasites. The key is the identification of
reliable markers for susceptibility and resistance.
In a similar manner, identification of the genes involved in protection
should provide producers with the information required to make informed
breeding decisions. The past few years have seen cattle producers become
more aware of selection for a variety of production traits, and have seen a
movement away from selection for a single trait. Cattle producers today judge
the genetic potential of bulls for many traits. The use of breeding values is a
common subject of interest to cattle producers. Providing producers with
reliable information on the performance of their cattle under parasite pressure
will allow them to make informed breeding decisions. Producers in areas of
high parasite pressure could choose not to use susceptible bulls, while those
in areas of less parasite transmission could use those bulls if they provided
other traits important in the overall breeding programme.
Finally, as our ability to manipulate the genome becomes more refined it
may be possible to genetically engineer cattle to meet the specific needs of a
given producer. The ability to do this with parasite resistance will depend
upon the exact mechanisms involved, the number of important genes and the
precise regulatory processes entailed. In any of these future schemes, it will be
important to first identify the gene loci involved in resistance, and to find
means to identify the resistance phenotype of individual animals rapidly and
reliably.
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